We have isolated mutations in the Drosophila ortholog of the human tumor susceptibility gene 101 (Tsg101) based upon their hyperplastic phenotype in the developing eye. A role for mammalian Tsg101 in tumorigenesis remains unresolved and it's mechanism in growth control poorly understood. Drosophila eye imaginal disc epithelia composed entirely of Tsg101 mutant cells continue to divide to form an undifferentiated tissue mass that exhibits defects in epithelial polarity. A similar phenotype is observed in imaginal discs that are mutant for one of the Drosophila neoplastic tumor suppressor class of genes (nTSGs). Each of the nTSGs encodes a protein whose localization and regulation are required for the establishment and maintenance of epithelial cell polarity. Thus, Tsg101 regulation may provide insight into the link between growth control and epithelial polarity, and the ultimate progression towards tumorigenesis. This research proposal will directly test 1) The major growth pathway that is deregulated by Tsg101 mutations and 2) The epistatic relationship between Tsg101 phenotypes (growth control and polarity defects) and the nTSGs. [unreadable] [unreadable] [unreadable]